Note: Descriptions are shown in the official language in which they were submitted.
~36~
The invelltion r~lates to pyri~-2-one derivatives, a
process for their manufacture, and pharmaceutical preparations
~hich con-tai~ Pyridone derivatives aild have an antiinfldrnm~o~y
action.
Kno~1n antiinfla~natory agents especially those f~r
treatin~ rheumatic diseases suEfer from the dis-
advantage o-f consid~rable side effects which rnanifest tilem-
selves, in a troublesome manner, in part;cular in the case of
prolonged treatrnent. There ;s, therefore, a need for com-
pounds having an ant1phlo~istic action which exhibit improved
gastric acceptab;l;ty.
The invention relates to pyr;d 2-one der;vatives of
the formula I,
R ~ R1 (I)
stereo;somers thereo-F and salts thereof with a phys;ologically
acceptable acid or~ ;f R2 represents a carboxyl group~ with
a base, ;n wllich formula
~ denotes hydrogen or alkyl having 1 to 6 carbon
atoms,
R2 denotes a ~CH-0, -COOR~ or ~C1l2~0-R5 group,
R4 representing hydrogen~ alkyl havin~ 1 to 12 carhon
atoms or ben~yl and
R5 representin0 h)~drogen~ alkyl having 1 to 4 carbon
atoms, alkanoyl ha~ g 1 to 9 carbon atoms, cyclo~
alkanoyl ha~.~ing 4 to 7 carbon 3~0ms~ alkoxycarbonyl
~,.
~3~
havintJ 2 to 5 carbon atomsr phenoxycarbonyl or a
benzoyl ~roup which can carry one or two halogcl1,
trifluoromethyl or all;yl or alkoxy substituents,
each of which has 1 to 4 carbon atoms, and
R3 represents 2-th;enyl~ 3-thienyl, tertO-butyl or a
phenyl group which can carry one or two substituents
denot;l1g halogen, trifluoromethyl or al~yl or alko~y,
each of which has 1 ~o b, carbon atoms.
Pre-Ferred compounds of the formula I are those in
which R1 represents methyi, ethyl or propyl and R2 denotes
a -Cl-l=O, -COOCH3, ~COOC2H5~ ~COOH or -Cl~2~0-R5 group. In
this connection R5 denotes hydroyen, a formyl, acetyl~ pro-
panoyl, n-butanoyl, 2~2-d;methylpropanoyl, n-octanoyl, cyclo-
propanoylr cyclobutanoyl, cyclopentanoyl or cyclohexanoyl
group, or a rnethoxycarbonyl, ethoxycarbonyl or benzoyl group~
the latter bein~ either unsubstituted or being monosubsti-
tuted by fluorine, chLorine, bromine, trifluoromethyl or
methyl.
In addition to the 2-th;enyl, 3-thienyl and tert.-
butyl groups, a suitable group for R3 ;s, in particular, thephenyl group which is either unsubst;tuted or carries one
subst;tuent, fluorine, chlorine, brornine, trifluoromethyl',
methyl and metho~y being preferred substituents~
Compounds of the formula I which should be singled
out particularly are those in which R1 represents methyl or
ethyl, in which R2 is ~CH=O, -COOCH3, ~COOC~Hs~ ~COOH or a
-CH2-o-R5 ~roupr R5 denot;n~ hydrogen, acetyl, propanoyl, 2
rr,ethylpropanGyl or n-butanoyl, and ;n which R3 is 2~thienyl~
phenyl~ ~-fluorophenyl or tert~-butyl.
~3~
. ~,
Compouncs of the formula I which are very particularly
preferred are those in which R1 represents methyl and R2
represents a ~COOC~13, ~COOH or CH-~0~ yroup and R3 denotes
2~tl1ienyl~ above all phenyl or ~ fluorophenyl.
The compounds o~F the general ~formula (I) also display
their essentia! propert;es in the form of the;r salts. Any
physiologically acceptable acids are su;table -For the pre-
paration o-f acîd addition salts~ These ac;ds ;ncludeO pre-
ferentially~ the hydro~en hal;de ac;ds, such as, -for example,
hydrochlor;c and hydrobromic acids, and also nitric acid
and also phosphoric acid or sulfuric ac;d~ Preferred orgai1ic
ac;ds are monoFunctional and biFunctional carboxylic ac;ds
and hya'roxycarboxyl;c ac;ds~ such as, for example, acetic
acia, maleic acid, oxalic acid, succinic acid~ fumaric acid,
tartar;c acid, ci.ric aci~, sal;cylic ac;d, sorbic ac;d,
lact;c ac;d and sulfonic acids, such as, for examplef p-
toluenesulfon;c ac;d, methylsul-Fonic ac;d, phenylsulfon;c
acid and 1,5 naphthalenedisulfon;c ac;d~ The salts of the
compounds of the formula (I~ can be obta;ned ;n a simple
manner by custornary methods of salt formation, for example
by dissolvin~ a compound o-f the formula I ;n a su;table ;nert
solvent and addin~ the acid, for example hydrochloric acid
or n;tr;c acid, and can be ;solated in a kno~n manner, for
exampie by filtration, and can, if appropriate~ be purified
2S by washing with~ or recrystall;zat;on frorn~ an inert or~anic
solvent.
The salts of the compounds oF the formula I with
physiolog;calLy acceptable bases are advantageously sod;urn~
potassium~ magnesium or calcium salts of those compounds
~3~
of the follnula I in which R2 denotes a carboxyl group~
The ;nvention also relates to a process -for the pre-
paration of the compounds of- the formula I, which comprises
reacting a compound o-f the formula II
~0
R3 (II)
with a compound of the formula III
X -- ~ ~ R2 (III)
h;ch forrnulae R1, R2 and R3 have the mean;ngs indicated
above and X represents haLogen, alkylsulfonyloxy, substituted
- 10 or unsubstituted phenylsulfonyloxy or the radical of a re~
active ester~ In particular, X denotes here chlorine, bro-
mine, methylsulfonyloxy, phenylsulfonyloxyr 4-metl1ylphenyl-^
sulfonyloxy or 4~chlorophenylsulfonyloxy or the radical of
a react;ve ester, such as trifluoroacetoxyr phenylcarbonyl-
oxy or methoxycarbonyloxy.
The process accordir.g to the inven~iorl is carriedout between 30 and 150C, preferably between 40 and 1Z0C,
in the presence of a base, in water or in an inert organic
solvent, such as N~N dimetl1ylformamide, N,N-dimethyl
acetamide~ d;rnetl1yl sulfoxide, aceton;trile~ N methyl
~--pyrrolidolle~ dioxaner tei:~al~ drorlJranf, ettlel~ /t Ill~?thyl~-2~
336~
pentanone, methanol, ethanol, isopropyl alcohol, propanol~
butanol~ pentanol, tert. butyl alcohol, methylglycol, d1-
methylglycol, dimethyld;~lycol, methylbutyldt~lycol or poly~
ethylene glycols. In add;lion, it is also possible ~o use
methylene chlor;de or an arornatic hydrocarbon~ such as benz-
ene~ chlorobenzene, toluene or xylene and also mlxtures of
t-he solvents mentioned aboveO
Examples of suitable bases are alkali metal or
alkal;ne earth metal carbonates, bicarbonates, hydroxides~
alcoholates or hydrides, such as sodium carbonate, sodium
b;carbonate, potass;um carbonate, sod;um hydrox;de, sodium
methylate or sodium hydride~ It ;s also poss1ble to employ
organic bases here, such as tr;ethylam;ne~ tr;butylamine,
ethylmornholine pyridine~ dimethylalninopyridine or quinoline~
The reaction also takes place with good yields under
conditions of a phase transfer reaction, by allo~ing the
reactants to react with one another in one o~ the above sol-
vents~ w;th vigorous stirring~ in the presence of a phase
transfer catalyst and either a powdered alkal; metal hydrox-
ide or a concentrated aqueous solution of an alkali metal
hydrox;de, and within a temperature range between 20 and
150C.
Examples of sui~able phase transfer catalysts are
tr;alkylbenzyiammon;uln or tetraalkylammonium halides~
hydroxides or bisul-fates, preferahly having up to 1? carbon
atoms ;n the alkyl radical, or crown etl1ers~ such as 12 crown~
4, 15-crown-5, 18 crown-6 or diben~o-18~crowl1-6~
h compound of the formula I in whicl1 F~2 is a -Cl~2 o-R5
~roup is advantageously prepared by reducing a compound o-f
36~
-- 7 ~
the formula T ;n which p~2 is a CoOR4 yroup, to give ~he ~CI-l20
group, which ;s then reacted with alkylating or acylating
agents to g;ve the CH~-O-RS group. Examples of sui.able
reduc;ng agents are lithium alum;num l1ydrider diisobutyl-
aluminum hydride or sodiurn borohydride, whicli are employeclin an inert solvent at temperatures between O and ~0C~
The alkylation and acylation reactions are carried
out in an inert solvent in the presence of a suil-able base
and at temperatures between 10 and 1~0C.
The preparation of compounds of the form-lla I in
which R2 is a CH-O group is advantageously effected by
oxidizing cornpounds of the formula I in wl1ich R2 is a ~CH20H
group. Oxidizing agents which are suitable for this purpose
are lead tetraacetate, chromium trioxide~ cl1rolnium~6 oxide
bis-pyridine complex, manganese dioxide~ Ni203.3H20, dimethyl
sulfoxide/tr;fluoroacetic anhydrider dimethyl sulfoxide/
oxalyl chloride, dirnethyl sulfoxide/cyclohexylcarbodiimide/
phosphoric ac;d, the pyridine/S03 complex or aluminum iso-
propoxide in combination with a carbonyl compound, such as
4-methoxybenzaldehyde, 2-chlorobenzaldellyde, cinnamaldehyde
or benzophenone. In addition to the solvents rnentioned abo~e
for the reaction of the compound II w;th the compound IXI,
glacial acetic acidr chloroform~ carbon tetrachloride and
petroleum ether are also additionally used~ llowever, a
cataly~ic oxidation with the aid of a catalyst containin~
a noble metal of the VIIIti- group, in particular platinum
and/or palladiunlr is also possiblen
The compounds of the formula II ~hich are reqlJired
. --
as intermediate products can be prepared ei~her in accordance
3~
~ith the process described by J. Thes;ng et al., Chem. Ber.
90, 7il (1957) or analo~ously to the instruct;ons giver, by
F~ ~rohnke et al. in Chem. Ber. 103, 322 et sec1,. (1970).
However, it is particularly acivanta~eous to react a compound
of the formula IV
R3 - C - Cl-13 (IV)
o
with an acrylic acid ester o-f the formula V
CHz - C~l - C - oR6 (V~
g
to give a compound of the formula V
R3 - C - CH2 - Ci~2 - CH~ ~ C - oR6 (VI
g 11
wh;c1~ I,en cycli~ed by medns o~ arnmon;a to cj;ve a cori7pour,d
of the formula VII
~ '
R3 1 (VII~
~ [
wh;ch is finally dehydrogenated to g;ve a compound of the
15 formula II. In the formulae ment;oned above, R3 has the
mean;ngs ment;oned in cla;m 1 and R6 is an alkyl rad;cal
having 1 to 6 carbon atolns.
The preparat;on of the compound VI froln the ketone
IV and th~ acryl;c acid ester V is carriecl out at ternpera
tures bet~Jeen 20 and 220C~ under alkaline cond;t;ons ;n
an inert solvent~ It is also possible to dispense w1th the
use oi solvents in this reaction and to carry out the reaction
~lithout a diluent. The base whicl1 is added to the react;on
~L~9~
_ 9 ~
mixture is preferably a pr;Mary amine, such as methylam;ne,
ethylamine~ propylam;ne~ isopropylamine, butylam1ne, cyclo-
hexylaln;ne or the ~ -N~alkylam;noprop;onate wl1;ch ;s formed
~rom the acryl;e ester and arn;ne usedO The rract;on 1s
5 earr;ed out ;n the presence of eatalyt;e amounts oF al1 aeid,
sueh as benzo;c ac;d, phenylsulfon;c ac;d~ toluenesulfonie
ae;d, salieylie ac;d~ acet;c ac;d or acryl;c ac;d~
The compound VI is then reac~ed with ammon1a in an
inert solvent or w;thout a d;luent a1: a temperature between
10 100 and 250C, preFerably in an autoclave, to g;ve the
eompound VII. The latter ;s then dehydrc)~enated usincJ a
dehydrogena~;on eatalyst, such as pallad;um-on-charcoal~
to give the compound II.
The cenpoundc of the for!nula III which are used as
1S starting materials are known.
It can be seen from the formula I that the colnpounds
aeeord;ng to the invention eonta1r at least one eenter of
asymmetry in the ~-position in relat;on to the o~y~en atom,
prov;ded that R1 does not denote hydrogen. The racema~es
of the Formula I which can be obtained if raeemic eompounds
of the formula III are used, can be resolved into the;r
optieal ant;podes in a eustomary manner. Th~s compounds
of the formula I in wh;ch R2 denotes COOH ean be trea~ed
us;ng an optically active base. The optieal antipodes of
2~ compounds of the formula I are obtained in an advantageous
manner if the startil1g mater;als of the formula IJX are
already optically active.
~ y v;rtue of the phar!nacological tests wh;ch follow
and the results obtait1ed tr,ere;n, the eompounds accordi~
1~33~
~ 10 -
to the ;nvention can be c!esignated suhstances which have
a pronounced ant;inflamnlatory action and, at the same time,
a low toxicity. They can~ therefore, be used as drugs having
an antiphlogistic action, in particular against rheumatic
diseases.
1~ Adju\~ant arthritis
_._ ___
The tests were carried out by Pearson's method
(Arthr;t. Rheum~ 2~ 440 (1~5~ The test animaLs used
were male rats of a l~is~ar Lewis strain having a body weight
betueen l30 and 200 9. The compounds to be compared were
administered orally every day from the 1st to the 5th day
of the test~ The anirnals in a control group only received
the solvent. Groups of 8 an;mals were used for each dosage
and in the ~ontrol groupn The criterion of action used was
the reductioll in the increase of pau volume compared w;th
that of the untreated control ~roup~ The ED50 values were
determined graphically from the dose activity curve.
2. Ga ~ on
The tests were carried out on groups of 10 male
Sprague-Dawley rats having a body weight of 200~300 9. The
feed was taken away, while free access to dr;nkin~ water
was permitted, from 48 hours before the aclministration of
the compounds to be compared until the animals were sacri-
ficed~ The rats were sacrificed 24 hours after the oral
adm;nistration~ and the stomachs were taken out, cleaned
under runiling water and ;nspected for lesions to tl-le illUCOUS
membranes~ r~ll les-iorls visible to the naked eye were coun~ed
as ulcers. Ttle propoltion of ar,imals havin~ ulcers a. each
dose ar~d the ub50 as specified by lichtfield and ~J;lcoxon
36~
(J. Ph~3rmacol. exp~ Ther. 96, 99 (1949)) were determ;ned~
3 . Acute t_x1 c~ty
Acute toxici1y W2S deterrl7ined by standard methods
using rats of the Sprac7lle-Dawley strain~ 6 anirnals were
5 used per dosaye. The LDSo values were determined by the
method of LichtF;eld and ~Jilcoxon~
CEI3
CEi - R2
2 ED50 50 50 50
Substance R Adj~Nant arthritis Gastric ulcers 7r~iex
__ _ ~ . ~ _ _
Sulindac 13.0 rng/kg 26.0 mg/kg 2
_ _ _ _~ . ... ._
Naproxen 15.0 mg/kg 21~0 mg/kg 2
~ . _ _ _~ .
Exar,ple 4 COOH 20.0 n~7/kg 175 nlg/kg 9
~ __ .. .. _
Exarrple 7 CC~C2H5 15.0 mg/kg 125 rr~/kg 8
~ ............... _ _ _. . . I
Exarriple 9 CHzOH 20.0 n~g/kg 220.0 rrg/kg 11
_ ._ ~
S~bstance50 TI D50/ED50)
Acute toxicity in~7ex
___ . ~_~
Naproxen 3~5 n~7/kg 26
__ _____ _ _
Exarn~)le 9 1,C00 rr~7/kg 50
~3f~
- 12 ~
The connpounds tested exhibited a clear advant&ge com-
pared w;th the known comparison folmulations sulindac and
naproxen on the basis of their excellent gastric tolerance
by rats, which constitute a model animal of good effeccive~
ness as an indicator of the most imporcant s;de effect of
this class of substances in humans. A therapeutic index
which is at least 4 times that of the compar-ison formulations
is derived from these tests. In add;tion~ the alcohol
(Example 9) has an acute tox-icity tLD50 1J00~ mg~kg) which
;s unusually good For antiphlogistic agent~ and is more than
twice the LD50 of naproxen (395 rng/kg)~
The drugs accordirlg to the invent-ion can be admini~
stered orally, rectally or parenterally.
Examples cf su;table scLid or l;quid ph3rmareutical
forms for formulation are granules, powders, tablets, dragees,
(micro~capsules, suppositoriesr syrups, emuls;ons, suspen~
sions, drops or injectable solutions and also form-llations
having a protracted release of active compound, which are
customarily prepared by using auxiliaries, such as excipients,
disintegrators, binders, coating agents, swelling agents,
slip agents, lubricants, flavoring substances, sweeteners
or solubilizers~ Lactose~ mannitol and other sugars, talc~
lactalbumin, gelatine, starchr cellulose and derivatives
thereof, vegetâble oils, polyethylene glycols and solvents~
such as, for instance, ster;le water~ may be ment;oned as
examples of aux;liaries which are ~requently used~
The formulatiorls are preferably prepared and admilli
stered in dosage un;ts, each unit conta1n;ng a specific dose
o-f active substance accord;ng to formula I~ In the case
~19~
- 13 ~
of solid dosage un1ts, such as tablets, capsules or supposi-
tor;es~ th;s dose can be up to 1,000 m9, but preferably 50
to 300 mg~ and in the case of injection solutions in the
form of ampuls ;t can be up to 200 mg, bwt preferably 20
to 100 mg~
Depending on the effect;veness of the compounds
according to formula I on hulnans~ the daily doses indicated
for the treatment o-f an adult patient suffering from inflam-
~ atory processes are 100 to 500 my of act;ve compound, pre-
ferably 200 to 300 mg, in the case o-f oral admin;strat;on,
and 20 to 150 m9, preferably ~0 to ~0 mg~ in the case of
;ntravenous admin;stration. Undrr certa;n circurnstances,
however, it is also possible to administel higher or lower
da;ly doces. The daily ~Jose can be administered either by
a single administrat;on in the form of an individual dosage
unit or several small dosage un;tsr or by the repeated admii-~i-
stration of subdivided doses at speci-fic intervals~
- ~he ;nvention is illustrated by means of ~he follow-
ing examples.
Example 1a
_
Methyl Dl-2-(6 phel1ylpyridirl-2~oxy) propanoate
34.2 g of 6-phenylpyrid-2-one are dissolved in 200 ml
of dimethylfrJrmamide~ 24~5 g of methyl Dl- ~-chloropro~ionate
and 27.3 9 of K2C03 are added successively and the mixture is
then stirred for ~ hours at 90C~ The reaction mixture is
then filtered while hot and the f;lter cake is washed with
a little acetone. The acetone and the ~olvent are removed
by distillation under redured pressure (dowl1 to 13 mbar),
and the residue is distillrd urlder a greatly redured pressure
1~3~
14 -
throuyh a 20 cm Viyreux column~ This g;ves 44.3 g (86% of
theory) of a colorless oil of bo;ling point 177C at 3 mhar.
Dimethyl sulfoxide, d;methylacetamide~ N-methyl~2-pyrrolidone
or ~irnethyldiglycol can also be used as the solvent, with
sodium carbonate as the base~ in the same procedure as des-
cribed above.
Example 1b
The following compounds of the formula I, listed
in Table 1, are prepared in accordance with Exa~ple 1a, but
us;n~ equ;valent quantities of the corresponding compounds
of the forrnulae II and III tDL-, D- or L~forrrl)~
.9;.3~
- 15 -
Ta~le 1:
~ O H ~ ~1
R H R
H
Comp~r~ X R3 R1 R2 . ... : ::
_ _ _ . . . _ . . . _ _
1.1 Cl CGH5 H ,~ M p.: 62C
_ _ . _ . . . _ 3 D,L
1.2 Br C6H5 CH3 -C-O-C2H5 B P 2 5 = 1 7 5-1 7 7 C
. .. ___ . D,I.
1.3 Br C6H5 CH3 O Mp.: 74C
-C-C-GH(c~3)2 D,L
__ _ _ . .... __ _ ___
1.4 Cl C6H5 G~3 ( 2)11 3 MP 39-LIOOC
~ ~ --~---- --- - - . - - ~---
1.5 C1 C6.Y5 CH3 -C-O-CH2-C6ll Mp 67-68 C
.. . _ . . . _ _ ,.. _
1.6 Br C6H5 C2H5 O
. .. _ ... _ . ___ . . ~
1~7 Br C6l~5 C2H5 -C-O-C2H5 Bp~ = 187C
. __ ~_ _ . .... ~
1.8 BrC6H5 ( 2)2~3 ~l
. -C-o-C~13
__ _~ ~ ..... _ __ ~ _. .. ~
1.9 Br C6~35 -~G~2)2~ 3 O BP~2 _ 185C
_ . ~ - ~C--O-C2~5 D,L
. . . _ _ _~_ _ _ _ ~._
~ 16 _
Tab l e 1 cont i n~led
___ _ _
Ccnpound X R3 R1 l R2
~ - _ _ . . . .. _ __
1 . 10 Br CG~5-CH (CE13 ) ~ ,~ . . . .
_ _ __ . _
1.11 -I2 C6H5 H C~2{> (C~ 2) 3 3
~3
_. __ _ , ~
1 . 12 _S02 t~6H5 H ~2~C 13 Bp O ~= 128-
a~3 _____ ~ _ ~ L,L
.1 3 B- C~ O C~i O ~ ~P 1 -
3 ~> -C~-C2H5 ~ 180~C
__ __ . __ __ ___
1.1 4 13r ~3{~ ~ c~3 -C-~C2.~15
~ _ _
1.15 Br CH3~ CH3 -C~C2H5 E~p 0 6 - 14~C
1 . 16 Br a~3 C~13 -'-~C2~15
__ ~ _ . ___ ._
1.17 Br (~ 3 ~{) CII
__AA_A_ .___ __ . _ _ . .. _ _
1.18 B~ ~ ~ U.~3 -C (}C2'H5 O 1 = 125-
___ ___ ,~
~336~
_ 17 _
Tab ~ ~ 1 cont i nued
_~____ _
C~I~b. d X R~ R 1 R2
_ __ _ ~
1 .19 3r F ~C-~ CE13 -C~C2~5 __~ __
1 . 20 Br Cl-(~ CT-I3 ~ (}C~5 Bpo 5 1 5 5 -1 6 0 C
__. _ __ _ __
1. 21 3r Cl C ~3 C C2~5 ~___~_ __
1. 22 Br ~ C l3 _~___ _
1. 23 Br Gi3 ~ O
¢~ C-~C~3
. S .
__ . __ _ __
1 . 24 Br 1 3 CH3 O
}~3C 1- -C-~C~15
CH3
_ ___ ~
1.25 Cl C,H~ Ct~ O Bp 0.8 150-154C
D ( + ) ~C~3 ~G] D = + 1 1 . 4
~G~C' 3)
~__ _ ___ -- _ ~ _ _ _ ._. .
1. 26 Cl ~ a~3 O
__ _ --C-'~I
1 . 27 Cl 1 3 aI3 O
1~3C-C- -C~3
~3 _ ~
.. .. __ _ _ ___ _.__... .. ____. , _ ___ ____._. .
_ 18 -
Tab l e 1 cont i nued
_~ ___
Comp~nd i ~ R3 . R1 R~
No. . ..... .. .. ..
1.23 ___ _ _____. ____.___ ___ . .... .
~1 -C-~-C1~3
1.2g Cl - - C~13 O_ _~
<~- ~-C~13
~3
___ ... _ _ _ __ __ .... __ _ ... _ ..... _ ._.___
1.30 Cl Cl~ G13 " Bp o 6 ~ 150-155C
D ( ~) C-OC~3 la] ~5 = * 11,4 ~C'Cl3)
_ ___~ __ ... ___ ... .. _
1.31 Cl H3C~ C~3 ~ Mp . ~102C
D(+) -C-{~3 ~]D = +1~.3 (CHC13)
.. . --_ . _ ~
1.32 Cl ~ C~ ~3 ~ Mp,: 125--l 26
D (~- ) -C-CX~I ~ ] D +14 - (CHC13 ~
1.33 C.l . __ . _ ___ ~ ___ _.______
D(+) F~ C~13 --C~ 3 Bpr 0 1 = 127-135 C
_ [a] 25 = + 11.2 (C~Cl3)
. _ _ __.___ . .
1.34 Cl F~ G O Bp - O ? - 145-150&
D~+) \_~r~ ~3 - C-CC21l5 [o]~5 = ~11,4 (CrlC
1.35 Cl . . G~ _ ~ ~~ 0 6 = 1so-l 52
L (-) ~._ 3 -C-OC2H5 [~] 25 -12,1 (c~c13)
1.36 Cl _~.. _ __ _____ _~_ ___.~_
--CI~O~-' C - ~ --C-CC2H5 Mp : 70 _
~_ ~ ._ _____ . __
.~936(~'~
~9
Example Z
____
Ethyl DL~2 C6~ dichlorophenyl)-pvrid;n~2~oxy~pro~arloate
24 g oF 6-(3,4~dichlorophenyl~-pyrid-2-one are added
in port;Gns, and while st;rr;ng and cooling, co a suspension
of 3 g of sodium hydride (an 80% strength d;spers;on ;n o;l)
;n 2DO ml of d;methylforrllaln;de at such a rate that the tem~
perature does not exceed 30Cr st;rr;ng ;s cont;nued at
40C unt;l ttle evolut;on of hydrogen is completer and 1~.1 9
of ethyl DL- ~ bromopropionate are then added dropwise and
stirr;ng ;s cont1nued For 5 hours at 80C~ After cooling,
the reaction mixture is poured into 500 rnl of ice water,
the mixture is extracted with methylene chloride, the
extract ;s worl~ed up in a customary manner and the residue
;s d;stitled under ~ greatly reduced pres~uren Th;s gives
25.5 g (75X of theory) of mat2rial of boil;ng point 1~0C at
n.3 mbar, melt;ng po;n~: 70C.
Example 3
_
DL~2-~6~phenylpyridin~2~oxy)~ethanoic ac;d
0.3 g of tetrabutylammon;um hrom;de is added to
a solution of 17u1 9 of 6-phenylpyrid-2-one in 1ûO ml cf
dirnethylformamide~ and 1~3 g of very finely powdered KOH
are added while stirr;ng vigorously~ 12~2 9 of ethyl chloro-
acetate are then added dropwi3e at 80C~ v;gorous stirring
is continued for a further 4 hours. 10 ml of water are addedr
stirr;ng îs continued for a further 30 m;nutes and the solvent
is removcd under reduceo pressure~ The residue ;s taken
up in 40 ml of waterr the solution is ac1di-Fied with 2 N H2S04
and the precipitated ac;cl ;5 filtered ofF wi-h suction~ dried
at 500C ;n a dryirlg cabinet and .hen recrystall;zed from
33~il)'~
~ 2~ _
di;sopropyl ether/hexane. This gives 1~ g, melting point
125~126C.
Example 4
. .
DL-2-~6-phenylpyridin-2 oxy)~propanoic acid
A mixture of 12.9 g of methyl DLw2-(6-phenylpyr;din-
2-ox,~?-propanoate, 2~4 g of NaOH and 10 ml of methanol is
heated at 80C for 30 minutes~ AFter cooling, the mixture
;s acidifed w;th 2 N H~SO~,~ and the precipitated acid is
dried at 50C in a drying cabinet and is then recrystalw
lized from di;sopropyl etlier/hexane. This gives 10.9 g (~0%
of theory) r melting point : 142-143C.
Example 5
Tlle following compounds of the formula I, listed
in Tab-~ 2~ al~e prepared i,l accordance W jth Example 4,. but
using corresponding quantities of compounds from Table 1
and NaOH.
~3~
- 21 -
Table 2
~1 0
~ ~0 - C - ~C - O - ~
Cornpour~ 1 R3 R1 Prepared -frcm M~p.: [ C] [a]D (CE~301i)
- . ~ Cc~lpound No _~--
2 . 1 C6H5 -C2H5 1 . 7 0
_._ .. _ . _ _
2.2 ~ CH3 1.22 154 oo
._ _ _ _
2 . 3 ~ CH3 1 . 21 ~ 0
. . _ . __,
.~ a- l 0O
2 . S H3C- IC- GH3 1 . 24 Oo
~ _
2 . 6 H C-~>-- CH3 1 .15 169 O
~ ~.. __. ~
_ ..
2. 7 F3C-~ Cli13 1 .19 0
_ ___ ~_~ ... .
D ( + ) Cl~>_ C 33 1 . 3 ~) 1 5 6 - 1 5 7 + 7 . 0
~ ___ ____
~93ti~
- 22 _
Tab l e 2 con t i nued
_
Ccnpound 3 ~1 Prepared fran M.p: [ C] k~D (C~.3n~)
No. Cony: ~uncl l\b.
__ .~ ._ ~_ ~ ._
D(+) ~I C-~ C~T3 1.31 169-170 ~ 7,2
. _ ~ . _ _ _
2 . 1 0 ~3C~ CH3 1 . 3 2 1 6 0 ~ 1 1 . 0
_ __ . _. ~ _ . ___ _ . _ _ _
2 . 1 1 ~ CE~3 1 . 33 13--1 19 t 9 . ~1
_ . __ _~___ ~._ . _ _ .
2 . 12 _ __ _ 3 1 . 3 5 1 25-1 2 6 -10, 0
_. ~_ ..
1~93~
- 23 -
Examp e_6
Dt~)-2~(6~- henyLpyridin 2-oxy)-propanoic acid
25.7 9 of methyl D(~-2~(6 phenylpyridin~2-oxy)-
propanoate, 20 ml of methanol, 20 g of l-l20 and 4.8 9 of NaOt1
are stirred at 75C for 3 hours and, after cooling~ are
acidified with 2 N H2S04. The precipi~ated ac;d is pressed
out on a clay plate and dissolved in diisopropyl ether, and
the solution is dried with Na~S04. A^Fter f-iltering~ hexane
;s added to the hot solution until cloudiness is formed. On
cooling, 18.5 9 (76% o-F theory) of product crystallize out,
melting point: 126C~ specific rotacion C ~25 - ~ 4
(CH30H).
Example 7
_
~ 2~(6-phcnylpyr,d-r;-2~oxy)-prop3noate
12aZ 9 of P(~-2-(6-phenylpyridin~2-oxy) propanoic
acid, in a mixture of 50 ml of toluene and 30 ml of ethanol,
are bo;led under reflux for 5 hours, the mixture of solvents
is removed by distillation and the residue is fractionated
under a greatly reduced pressure~ This yives 11~ 2%
o-f theory) of product, boiling point 138-142C at 0~5 mbar,
specific rotation ~320 = 1ODOO (CHCl3).
Example 8
6-Phenylpyridin-2--oxyethyl ethyl ether .
A suspension of 8.6 9 of 6-phenylpyrid~2-one. 0.5 9
of tetrabutylamrnonium bromide, 5.4 g oF Z-chlorodiethyl ether,
100 ml of toluene and 20 ml of 50% strength sod;um hydroxide
solution is vigorously stirred -For 5 hours at 100~. After
cooling, 30 ml of water are added~ the orgarlic phase 1s
separated of~, r;nsed ~Jith 2 N NaOH and dried over Na
36~
- 2~ -
the solvent ;s removed under reduced pressure and the residue
;s distilled under a greatly reduced pressure. This gives
7.9 9 t66% of theoryj of- a colorless oil.
Example 9
___
DL-2 ~6-phenylp~r~__n-2-oxy~ _ nol
A solution of 13.6 g of ethyl DL~2-(6-phenylpyrid;n
2-oxy)~propanoate in 30 ml of absolute diethyl ether is added
dropwise, at room tempelature and !Jhile st;rring, to a sus
pension of 2~05 g of L;thium alum;num hydride in 75 ml of
absolute d;ethyl ether, and the m;xture is st;rred under
re-flux for 1 hour. After cooling, the m;xture is hydrolyzed
w;th water and acidified l~ith 10% strength sulfur;c acid,
and the aqueous phase is saturated with NaCl and is separated
off, the remainder is extracted with ether, the combirled
organic phases are dried over Na2S0~ and the solvent is removed
under reduced pressure. 1he residue is distilled as described
in Example 1a. Th;s gives 10.9 g ~95% of theory) of product~
boiling point 181C at 6-7 mbar.
Example 10
D(~)-2 (6 ~ din-2 oxy _propano_l
11.0 g (96~ of theory) of product, boilin~ point
180C at 6 mbar, spec;fic rotation C~ ~20 ~ -~2.1 ~CHCl3),
are obtained ;n accordance with Example 9, but-using 1209 g
of metl1yl D(1-)~2 ~6~phenylpyr;din 2~oxy)-propanoate~
Example 11
-
The follo~ g compounds of the formula I, listed ;n
Table 3, are prepared ;n accordance w1th Example 9~ but us;ng
corresponding quantities or compounds from Tablc 1 and lithium
aluminum hydr;de:
i~L936~'~
-. 25 _
T a b l e 3
/~ C) - C - CH2 ~ C~E-I
R3 ~!
C~o~Jn,d I ~3 R Prepared frcrn
No~ i 1 Con~nd No.
. . . ~ __
3~1 C6~5 ____ 1.7
3 . 2 ~3\ C~3 1 . 22
. ___ _ . .. , ~
3.3 (~l3~ _ Cii3 1.16 ___
3 . 4 ~C:L CH3 1 . 21 ~T
.. _ ~ --C~3 1. 2~ _~
CH3
3 . 5H3('~ 3 1 .15 M p ~ 55 C
~ __ ~ . . ~ D, L
3 . 7CF3-~ C~-13 1 .19
~.____ ____ ___ ._ _ ~ _ . . __
3 . 8Cl~ C~13 1 . 2 0 M p 61 C
__ .. __ _ . . _~__~_ __._ . D, L ____
3, 9 H3C~C)~-- C~3 1 ~14 M p ' 53C
__ ~ _____ __ _ _ ._ ___._.__~ D, ~
~ 93~
_ 26 _
Tab l e 3 cont i nued
.__ ____ .
Car~ nd~R3 1 I Prepared frcm
No. I Canpound No.
. _ _ .,,. . ___
3 .10Cl-- ~ C~ 1 . 30 2
D(~) ~ ~ ~ 5 = +1 / (
3.11 CH 1.31 Mp.: 55 C
D ( + )ll C -~ 3 [cl ] D = + 2 . ~ 'C'13 )
_~_ .. ~ _~_................. __ __ _
3.12 H C~ CH3 1.32 Mp.: 5~ C
D(+) 3 ~C~]D = + 2.~', (ClICl3)
___ _~ . . ~ . .~_____
3.13 F~ CH3 1.18 Bpo 1 = 150C
. _~ . __ __ _ D, L _ ___
3.14 ~ S~3 1.33 BP'0~1 ~ 150 C
D t ~ ) _ _ ~ D + 1 . 7 ( l~iCl 3 )
_ _ ___ _ _ _ _____
3.15 ~ C~3 1.35 Bpo 6 = 165&
~~ . ~ 5 - -2.2 (C-:Cl
~L ~93~
~ 27 -
_ample 12
DL-2-(6 phenylpyridin-2-oxy)~propyl acetate
2.3 ~ of acetic anhydride are aclded dropwise at room
ternperature and while stirring to a solution oF 406 ~ of DL-
-2-(6-phenylpyr;d;n-2 oxy)-propanol (from Exarnple 9~ in 10 ml
of pyridine, stirring is continued for 4 hours a~ 6nc and
the m;xture is cooled and poured ;nto 50 ml of ;ce water~
which is extracted w;th CH2Cl2 and the extract is worked up
;n a custornary manner~ The residue is d;st;lled under a
greatly reduced pressure~ Th;s gi~es 4.3 CJ t80~/~ 0~ theory~
of a colorless oil~ boiling point 153--155C at 0~3 rnb~r.
Example 13
___._
The following compounds of the fornlula I5 listed ;n
Table f-~, are prepared ;n accorc!~nce with Exampl.e 12r but
us;ng corresponding quant;ties of compounds from Table 3 and
acet;c anhydr;de.
3~
- 28 --
Table 4
J~--C - CH - O - C - C f l 3
R3
,
CaTpo~rcl . R3 Prepared fr~
No~ Cc~npourd No~
~ . __~__ _
4.1 ~ 3.2 ~
._ , _ _
4.2 ~13 3.3
~ _.. ___
4.3 (~Cl 3.4 ___~_
4 . 4CH 3 3 . 5
H C - C -
C~3 ~ . .
_ .
4 . 5H 3 C~>- 3 . 6
_._ ___ _ ___
4 . 6F3 C-~ 3 . 7
___ _ __ ~
4.7-- Cl-~ 3.8 .
_ ____~._ __ _ ._
4 . 8 H3 C-O-(~ 3 . 9
__.__ _ _. ____~____ _~
D ( ~ ) L F~ 3 . 1 4 ~
336~'~
Example 1/~
DL-2-t6-phenylpyridii1-2-oxy)-propyl isobutyrate
A solution of 201 g of isobutyryl chloride -in 5 ml
of methylene chloride is added dropwise, while st;rring and
cooling at 0C, to a solut;on of 4.6 g of DL~2-~6-phenyl~
pyridin-2-oxy)-propanol ~frorn Example 9) in Z0 rnl of methyl.
ene chloricle and 2.2 g of tr;ethylan1;ne, ancl the m;xture is
allowecl to warm up to room temperature and stirring ;s then
cont;nued under reflux for 2 hoursu After cool;ng, tl-e rn;x~
ture is extracted by shakiny ~lith water, tl1e extract is
worked up in a customary manner and the residue is d;stilled
under a greatly reduced pressure~ This gives ~ g (67% of
theory) of product, boiling point: 155 158C at 0.2 mbar.
Example 15
The follow;ng compounds of the formul.a I, listed in
TabLe 5, are prepared in accordance with Example 14, but
using equivalent quantities of compounds frorn Examples 9
10 or Table 3 ancl a corresponding acyl chloride:
Table 5
_
,
~9360;~
_ 30 -
Tab l e 5 c.ont i nuPd
_._______ __
C~T~R2 R3 ¦f rorn
No. . Compoun~l
__ ______ , _.___ (1~.) __ ___._
5 .1 O <~>Examp le P 0 2=155-1 58C
-c~2~c- (c~2) 2-CH3 9 D,L
~ ~__ ---- _ __ _ __
5.2 O Example B,oO 5= 160-165 C
-c~2~C--tcrl- -bU~ ~ 9 D, L
. ~ _ . _ _ ___ _ _ ____
5 . 3 O . . - E xamp l e Bp 0 6=175-1 80C~C
- ---- C~2 ~C~CH2~G~3~~C~3 ~C(CH ) _ ___ D~L
5 . 4 O Exarnp le Bp .0 3=1 65-1 70 C
_CH;~_O-C--C2H5 ~ 9 D,L
5 . 5 _ _ _ E x amp i e; Bp = 17 0-1-7~ C`
-CL~2~ C~ ~ 9 . D ~ O ~ 5
_ _ . _ _ ___ _ _ _
5.6 O Example
{~2{~-C~ ~ 9
. _ . ___ _._ _ .___ . _
5. 7 O Examp le Mp : 62--64 C
_CL~2~C_C~;3 ~ 9 D, L
5 . 8 O --- ~ _~ E xamp l e Mp : 68~70C
C.~2~}C~ ~ 9 D, I,
5 . 9 O - - ~ _ _ . E x a m p l e _ ~ . . - __
Cf~2--(}C~> <~ 9 D,L
_ _ _ , _ _ _ _ ~ _.__ . _
5 . 10 O E xamp l e Mp ~ 6~3-69 C
2~ C- ~3 ~Cl ~ 9 D, L
~ _ ~._ _~ _.__ _ _
5. 1 1 _ Example
-C~2~C--~ 3 C~
_~_ ~ ~ _.. ... _ ~_ ____ .
.
1~936~
_ 31 -
Tab l e 5 c_nt i n ued
C0,7~a ncl R2 R3 Prepared
Nb~ f roin
Co~ound
~ _ __ __ , , _ _ _~10 ) _ .. __ _ _.__
5.12 0 Example
-C~2~C4~ 0~-I3 (~ 9
. _ .. .. _ _ _, _............... ._ _.
5 . 13 -C~ -0 C- ~ CF ~ E x amp l e
. _ ... . ------ ' ' ___ _____ _
5.1'1 O C~l Example
-CH2-0-C ~> ~ 9
. _ . . ~ _ _ .. _ ~
5. 15 ., _ Example Bp 0 3=153-155 C
D~+) CE~2~C-CH3 ~ 10[~)25 = ~3,4
((:E-IC13)
_ _ . _ _ .. __. . .......... ____
S.16 0 Example Bp 165-168C
D(+) -C~H2{~C-C2H5 ~ 10 0~25 0
_ _~ ~ (C~,C13)
5 . 17 = ~ _~ E x a mp l e o 2= 155-1 5bC
D(~-) -~I2-~C-C3~7 ~ 10 [C~J~5 = +3.2
(G'IC13 )
. _ . _ . . __ _ ______
5.18 O Example E3p 0 2=155-158 C
D(+) -c~I2~~c-G~(G'I ) ~ 10 [Q]25 = + 3 3
_ __ _ _ ~ _ _ - _ 3 ___
5.19 0 3.1
D ( +; CH2C) -C-C'H ~ _
_ __ _ . __~ _ _____ ~
5.20 0 3.14
V ( ~ ) "
5.21 _ ~___ ~___
D (+) -C~2~C-C~ (C7~3 ) 2 - F'-~>- 3 .14
. ~ __ __. ~ ~
~93~
~ 32-
Tab l e S cont i nued
Prepared
Ccrrpound R2 R3 f rom
No. Ccmpo~md
5 . 22 . ~___ _ __ _ ___(No. )
D (+) -CH2~C-C3~i7 ~) 3 . 14
. __ ___... __ __ ~_
5 . 23 O M p: 75-76C
D(l) " 0~ Cl~- 3.10 [~)D = + 6.0
. ~_~ . __ ~ (~ICl3 )
5. 2~ O Bp = 173-17~1 C
D (+) ~, Cl-~ 3 .10 ~5
. C~ICl3)
_ ____ . . .. ____
36V,'~
- 33 -
Exann~le 16
DL~2-(6-phenylpyr;din 2-oxy) propyl methyl ether
A solution of ~.6 9 of DL-2-(6-phenylpyrid;n-2-
oxy)-propanol (from Example ~) in 5 ml of absolute telra-
hydrofuran (THF) is added dropwise, while stirr;ng at 20C~to a suspension oF 0.6 9 of YaH (~0% strength dispersion
in oil~ în 30 ml of absolute THF, stirr;ng is continued until
the evolut;on of hydrogen is complete, the mixture is cooled
to ûC, a solution of 2.8 g of methyl iodide is added drop-
wise, and the mixture is allol~ed to ~Jarrn up to room tempera~ture and is then boiled under reflux for 2 hours. After
cooling, the solvent is removed under reduced pressure, work-
ing up ;s carried out in a customary manner with water/methyl-
ene chlor;de ~nd the residue is d;stilled under a ~reatly
reducec! pressure. This gives 3.9 9 (8bx of theory) of pro-
duct, boil;n~ po;nt 128-131C at 0.5 mbar.
Example 17
~L-2~(6-phe _lpyrid;n-2 oxy)-propyl butyl ether
4.3 9 t75% of theory) of this product are obtained
;n accordance with Example 16, bu~ us;ng 4.~ 9 of DL-2-t6-
phenylpyr;clirl-?-oxy)~propanol ~from Exanlple 5) and ?..7 g
of n butyl bromidei
Example 1 8
3L~2-(6~phenylpyridin 2~oxy~-propanal
?5 The exper;lment is carr;ed out under nitrogen as an
;nert gas. A solut;on of ~.78 ml of dirnethyl sulfox;de in
10 ml of ai~solute methylene chlor1de ;s added dropwise, wllile
stirr;ng at -hOCo to a solution of 2.32 ml of oxaLyl chloride
;n 25 ml of absolute methylene chlor;der stirring is contirl-led
36~
~ 34 -
for a further 5 m;nutes and a solu~;on of 3.7 g of DL-2-(6
phenylpyridin-2-oxy~ propanol (from Example 9) in 20 ml of
absolute methylene chloride ;s then added all at oncen Stir
ring is then continued at -60C for Z0 minutes, 1~4 ~l of
triethylamine are added, the mixture is allowed to ~Jarm up
slo~lly to room teMperature and 50 rnl of water are then added
and the product is worked up in a customary manner. The
residue is taken up in 40 rnl of ether, the sol~ltion is fil-
tered through Celite and the solvent is removed under reclllced
pressure. This gives ~ g (S6'~ of theory~ of a colorless
oi l.
Examples of the preparation of compounds of the fornlula XI
Example 19
6-Phenylpyrid~2-one
__
1~ a) Methyl 5-phenyl-5-oY~opentanoate
3,220 g of acetophenone, 484 g of rnethyl acrylate,
80 g of isopropylamine and 2.7 g of benzoic acid are h~ated
at 200C for 3 hours in a 5 liter autoclave. In addition to
unreacted methyl acrylate and acetophenone, the subsequent
distillation under reduced pressure gave 640 g of product,
boiling point 175C at 7~5 mbar (55~5% of theory relative
to methyl acrylate).
b) 6-Phenyl-3,4 dihydropylid-2-one
300 g of methyl 5 phenyl-5-oxopentanoate are heated
to 180C in a 500 ml flask equipped with a descending con~
denser. Ammonia is then passed in for 3 hours. In the
course oF this the \~ater and methanol formed d1stil c,Ff through
the descending condenser~ After cooling~ the reactiol1 m1xture
solidifies to give a mash of crystals. The mixt-lre is fil~ered
~93~13'h
- 35 -
with suction and 130 g (53% of theory3 of product, melt;ng
point 158C, are obtained. The mother liquor contains
mainly unreacted starting material.
c) 6 Phenylpyrid-2-one
250 ml of methylbutyld;glycol and 5 9 of catalyst
(2% strength Pd-on~charcoal) were added to 30 g o-f 6-phenyl-
3,4~d;hydropyrid~2-one in a 500 ml glass flask equ;pped with
a stirrer, a thermometer, a descending condenser and a gas
meter. The apparatus ~las flushed w1th nitrogen and the
methylbutyldiglycol was then heated to reflux temperature
In the course of ~h;s ~.3 liters of exit gasr composed of
90% oF hydrogen, were formed dur;ng 5 hours. The apparatus
was aga;n flushed ~;th N2; ~he solution was freed from
the caLal,st by filtration ~!hi!e hot~ ~n coolln~; 25r3 9
(82X of theory) of product, melting poin'c 198C, crystallized
out from the mother liquor.
The catalyst can be used againO Even a-Fter being
employed ten times, the yield of 6-phenylpyrid~2~one is
approxilnately 80%~
Z0 Example Z0
-
The following compounds of 'he forlnula II, listed
in Table 6, are prepared in accordance with Example 1~, but
using corresponding quantit;es of a kecone of the -formula
O
R3-C-CH-~ and of an acryl;c acid ester of the formula
Cll .
Cl12=Cr~~C~O~C~l~5:
i~93Ei~
36 _
Table 6
___
Il L
N~O
H
Con~nd R
No. 3 . Melt ing poi n-t; ~ (3
~ .__ ___.__
6. ~ M3C;~_
, _______, _ . _ ______
6 . 2 C~13O~ 172-176 a~
6 . 3 _ . .. . . _ 1 7 0 - 1 7 5 a )
~'3C-~
__ _ __. _ _
6.4 ~CT~3
. . C 1 _ _._ ._
6.S Cl~
~ _ _ ___ ~
6.6 F~- . 178-183 a~
. ~ _ ~ ~
6 .7
F3C4
____ ~_____ __ ~
6 . 8 . 2G3-204
_ Cl~-
_~ __ . _ .~_ _ _ _
.
a) Melting point not sharp because of slight impllrities in
the cc>rresponding 3,l~,.5,6-tetrahydropyridin-2-ones.
. ,
,
37 _
Table 6 contin~led
_ _
C onpamd; R3 ....
No. . Melting point: Lc]
_ _. ~ .~
6.9 ~-Cl
6. 10 CH3
CH3
6.11 ¦
__
